The large-scale failure of a handful of drugs repurposed for COVID-19 hasn’t slowed efforts to find existing – and new – therapies as well as vaccines that can fight the pandemic, with research updates continuing to roll out.
Interim data from the Solidarity Therapeutics Trial coordinated by the World Health Organization (WHO) show Foster City, Calif.-based Gilead Sciences Inc.’s remdesivir (branded as Veklury) as well as hydroxychloroquine, lopinavir/ritonavir, and interferon regimens apparently “have little or no effect” on 28-day mortality or the in-hospital course of COVID-19 among patients admitted.
Gilead, about a week ago, pointed to the publication in The New England Journal of Medicine detailing results from the 1,062-patient phase III study of remdesivir led by the National Institute of Allergy and Infectious Diseases. Preliminary data were made known in May, but the final set of data covers about 1,060 hospitalized patients. Those given remdesivir recovered five days faster on average, and in patients with severe disease, seven days faster. The severely ill patients made up 85% of the total study population. Remdesivir reduced the likelihood of patients progressing to more severe stages of the disease where they would require new or additional oxygen support. In the largest group of patients, those on low-flow oxygen, there was a significant reduction in mortality in a post-hoc analysis.
SVB Leerink analyst Geoffrey Porges said in an Oct. 9 report that “the fine print of the results is perhaps less encouraging than the top line. While remdesivir seems to accelerate clearance of virus and resolution of symptoms, it did not improve survival at 29 days which is the endpoint of most importance in the end (earlier endpoints are confounded by patients still in the hospital, still on oxygen or ventilation).”
In any case, the Solidarity study paints a different picture of remdesivir and other treatments. Involving more than 30 countries, the experiment checked effects on overall mortality, start of ventilation, and duration of hospital stay. In 405 hospitals, 11,266 adults were randomized, with 2,750 allocated remdesivir, 954 hydroxychloroquine, 1,411 lopinavir/ritonavir, 651 interferon plus lopinavir, 1,412 only interferon, and 4,088 no study drug. Compliance was 94% to 96% midway through treatment, with 2% t 6% crossover. In all, 1,253 deaths were reported (at median day eight, interquartile range 4-14). Kaplan-Meier 28-day mortality turned up at 12% (39% if already ventilated at randomization, 10% otherwise).
The regimens proved unhelpful “as indicated by overall mortality, initiation of ventilation and duration of hospital stay,” Solidarity researchers concluded. “The mortality findings contain most of the randomized evidence on remdesivir and interferon, and are consistent with meta-analyses of mortality in all major trials.”
Turku, Finland-based Faron Pharmaceuticals Oy is not giving up on interferon beta-1a in COVID-19, delivered by a different route than in Solidarity. Findings from the WHO experiment “support our long-held view that interferon beta-1a is likely to be ineffective when given subcutaneously, CEO Markku Jalkanen said. “The science behind [Faron’s] Traumakine and its potential to prevent multi-organ failure through the upregulation of the key endothelial enzyme CD73 is compelling, and we continue to believe that an intravenous [I.V.] formulation of interferon beta-1a is what patients need to strengthen the body's own interferon beta signaling,” and thereby “provide optimal exposure to the lung vasculature.” Specifically, the I.V. approach achieves more than 150 times higher peak concentration there.
Pharmamar making strides
A global trial at more than 200 sites in 19 countries is testing Traumakine and other treatments for community-acquired pneumonia, including in COVID-19 patients. Faron is also supporting a potential phase II/III U.S. effort to probe the potential of the drug against COVID-19. To be conducted at Harvard Medical School’s Beth Israel Deaconess Medical Center, the effort awaits finalized funding arrangements and regulatory approval. It will focus on intensive-care patients with acute respiratory distress syndrome caused by viral infections that include COVID-19 and influenza. Traumakine will be tested against placebo and dexamethasone.
Another company keeping the interferon faith is Southampton, U.K.-based Synairgen plc, with an inhaled version known as SNG-001. The company disclosed positive results this summer from its double-blind, placebo-controlled phase II trial in hospitalized patients, and the study, called SG016, was extended to include 120 more patients with confirmed COVID-19 in the home environment. CEO Richard Marsden, responding to the Solidary results, told BioWorld that his firm’s “feeling was that if it was going to work in injection it was going to work through a more subtle boost to the immune system, but the results today suggest this isn’t the case.” With SNG-001, Synairgen is “rolling straight into a phase III trial in 900 COVID-19 patients globally,” working with partners “to manufacture enough drug to run the trial and, more importantly, to put drug on the shelf so that it can get to patients quickly if the trial is successful.’
Chalking progress with its non-interferon COVID-19 treatment was Pharmamar SA, of Madrid. The company said its Aplicov-PC1,2 trial with EF1A blocker Aplidin (plitidepsin) for hospitalized patients met primary safety and secondary efficacy endpoints. Three patient cohorts, with three Aplidin dose levels (1.5 mg, 2.0 mg, and 2.5 mg), were evaluated. The patients' viral load was evaluated quantitatively at the same center at the beginning of treatment and on days four, seven, 15 and 30. The drug yielded a substantial reduction of the viral load in patients between days four and seven, with the average drop on day seven at 50% and on day 15, 70%. More than 90% of the patients included in the phase I trial had medium or high viral loads at the start. Pharmamar said 80.7% were discharged on or before the 15th day of hospitalization, and 38.2% before the 8th day. Protocol required that patients stay in the hospital for a minimum of a week.
On the COVID-19 vaccine front, New York-based Pfizer Inc. provided the latest in the form of an open letter from CEO Albert Bourla. He said the company would not apply for emergency use authorization until the necessary data are in hand. “Our internal standards for vaccine safety and those required by regulators are set high,” he wrote. “In the instance of emergency use authorization in the U.S. for a potential COVID-19 vaccine, FDA is requiring that companies provide two months of safety data on half of the trial participants following the final dose of the vaccine. Based on our current trial enrollment and dosing pace, we estimate we will reach this milestone in the third week of November.”
AI to the rescue?
Solidarity’s brisk pace proves that it’s possible to carry out large-scale, international studies as the pandemic marches on. With almost 500 hospitals open as sites, the global platform established by Solidarity is ready to test other COVID-19 prospects. Antivirals, immunomodulators and anti-SARS COV-2 monoclonal antibodies are undergoing investigation, the WHO said.
As the profile of artificial intelligence (AI) grows in biopharma, some are touting its utility in the repurposing push. A recent paper in The Lancet found “a strong rationale for using AI-based assistive tools for drug repurposing medications for human disease, including during the COVID-19 pandemic.” One study that deployed a network-based methodology to quantify the interplay between the virus-host interactome and drug targets in the human interactome network suggested no fewer than 16 repurposed drug candidates for potential treatment of the virus. Published in March in Nature, the paper concludes that the authors’ method “can minimize the translational gap between preclinical testing results and clinical outcomes, which is a significant problem” in reaching solutions for the COVID-19 outbreak, then emerging. “From a translational perspective, if broadly applied, the network tools [described in the paper] could help develop effective treatment strategies for other emerging viral infections and other human complex diseases as well.”
With many scientists scrambling to come up with treatments and vaccines for COVID-19, some are exploring the finer points of the virus – factors that might foretell a better or worse course for any given patient. Two studies published October 14 in Blood Advances suggest that blood type plays a key role. Specifically, patients with type O blood are at less risk of contracting the virus, and may have a less difficult time if they do. The discovery isn’t exactly new; a paper in the New England Journal of Medicine in June pointed in the same direction.